Helicobacter pylori is a bacterium that infects the stomach lining (or gastric mucosa) of perhaps half the world's population. Spiral organisms were first microscopically observed in human gastric mucosa in 1906. However, H. pylori was not successfully cultured until 1982. Infection with the organism is usually chronic, and results in continuing inflammation of the gastric mucosa. The infection is often asymptomatic. However, in association with other cofactors, a proportion of infected people go on to develop sequelae including peptic ulceration of the stomach or duodenum, gastric adenocarcinomas and gastric lymphomas. Peptic ulcer treatment studies have shown that cure of H. pylori infection is associated with a dramatic reduction in the relapse rate of this usually chronic disease. Long term infection with H. pylori leads to the development of chronic atrophic gastritis, which has long been recognised as a precursor lesion in the development of gastric cancer. Thus, a number of studies have linked preceding H. pylori infection with an increased risk of developing gastric cancer. Therefore, eradication of current infection and prevention of new infection with this organism has the potential to significantly reduce the incidence of diseases that result in considerable morbidity and mortality (In Helicobacter pylori Biology and Clinical Practice. 1993. Edited by C. Stewart Goodwin and Bryan W. Worsley. Published by CRC Press; Halter et al 1992, Yale J. Biol. Med., 65:625-638).
Infection with H. pylori is difficult to treat. Current experimental therapies for treating the infection have problems with efficacy and significant levels of adverse effects. There are no prophylactic measures clinically available. A solution to both the prevention and treatment of H. pylori infection would be the development of an immunogenic preparation that, as an immunotherapeutic, treats established infections, and as a vaccine, prevents the establishment of new or recurrent infections. Such a preparation would need to induce effective immune responses to protective antigens, while avoiding induction of responses to self-antigens or other potentially harmful immune responses. This may be achieved by identifying the specific protective component or components and formulating immunotherapeutic or vaccine preparations including such component(s).
The identification of such protective components of an organism is often accomplished using an animal model of the infection. Initially, there was no animal model available of human H. pylori infection. However, one such model was developed using a closely related organism, H. felis, and specific pathogen free (SPF) mice (Lee et al, 1990, Gastroenterology, 99: 1316-1323). This organism is able to colonise the gastric mucosa of SPF mice, where it establishes a chronic infection with many of the features of H. pylori infection in humans. H. felis infection in these mice induces a chronic gastritis and a raised immune response. As in the human case, this response is not effective in curing the infection.
The above model has been used to demonstrate that oral treatment of H. felis infected mice with a preparation containing disrupted H. pylori cells and cholera toxin as a mucosal adjuvant can cure a significant number of the infected mice (Doidge et al, 1994, Lancet 343(i): 914-915. This effect is likely to be mediated through an immune response to cross-reactive antigens possessed by each of the closely related Helicobacter species. Two such cross-reactive antigens have been identified by Doidge et al (WO 95/33482) as the microbial enzymes urease (Clayton et al, 1990, Nucleic Acid Res., 18(2): 362) and catalase (Westblom et al, 1992, Eur. J. of Clin. Microbiol. Infect. Dis., 11: 522-526).
Recently, an H. pylori (Sydney strain)/mouse model of human H. pylori infection has been developed and used by the present inventors to confirm that catalase, in particular recombinant catalase, has utility as a protective antigen. However, despite this encouraging finding, Helicobacter catalase may not be seriously considered as a therapeutic vaccine candidate due to its high homology with human catalase and associated potential to induce autoimmune disease.